title: PAMAM dendrimer derivatives as a potential drug for antithrombotic therapy.
abstract: Platelets are anucleated blood cells that play an important role both in the pathogenesis of atherosclerosis and subsequent thrombosis. Dendrimers have attracted great interest in biomedical applications. However, their interactions with cell compounds and compartments are nonselective, thus causing cytotoxicity and hemotoxicity. We derivatized PAMAM G4 and G5 dendrimers to evaluate their interactions with serum metabolites, their effects on the viability of red blood cells, and their antithrombotic properties. PAMAM G4 and G5 derivatives showed better hemocompatibility than the PAMAM G4 and G5 dendrimers without any derivatization (NH₂). PAMAM G4-Arginine-Tos and G4-Lysine-Cbz act as potent inhibitors of platelet aggregation induced by ADP. PAMAM G4-Arginine-Tos also showed inhibition of platelet aggregation induced by collagen, TRAP-6 and arachidonic acid. Moreover, G4-Arginine-Tos present inhibition of platelet secretion and thrombus formation under flow conditions. Based on our study, the PAMAM G4-Arginine-Tos derivative is hemocompatible and produces desirable antiplatelet and antithrombotic effects. Thus, this compound has potential applications as an antithrombotic drug or a drug delivery vehicle.
authors.affiliation: Nanobiotechnology Division at University of Talca, Fraunhofer Chile Research Foundation-Center for Systems Biotechnology, FCR-CSB, Talca, Maule, Chile; Laboratory of Asymmetric Synthesis, Institute of Chemistry and Natural Resources, University of Talca, Talca, Chile.
authors.forename: Esteban
authors.initials: E
authors.lastname: Durán-Lara
authors.forename: Luis
authors.initials: L
authors.lastname: Guzmán
authors.forename: Amalraj
authors.initials: A
authors.lastname: John
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fuentes
authors.forename: Marcelo
authors.initials: M
authors.lastname: Alarcón
authors.forename: Iván
authors.initials: I
authors.lastname: Palomo
authors.forename: Leonardo S
authors.initials: LS
authors.lastname: Santos
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D050091:Dendrimers; D005343:Fibrinolytic Agents; C104700:PAMAM Starburst; D003094:Collagen
keywords: Antithrombotic; Hemocompatibility; MALDI-MS; PAMAM derivatives; Platelets